Lack of vaccination, severe illness tied to higher risk of long COVID

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A US military study suggests that people who are unvaccinated against COVID-19 and those with moderate or severe infections are at significantly higher risk for persistent symptoms for 1 to 6 months.

In the observational study, published yesterday in JAMA Network Open, a team led by researchers from the Uniformed Services University of the Health Sciences in Maryland estimated the risk of long COVID and greater healthcare use among 1,832 infected adults enrolled at a military treatment facility.

The researchers extracted data from the Epidemiology, Immunology, and Clinical Characteristics of Emerging Infectious Diseases with Pandemic Potential study, which tracked adults for 1 year after testing positive for COVID-19 from Feb 28, 2020, to Dec 31, 2021.

The study period spanned the dominance of the wild-type and Delta SARS-CoV-2 strains. Patients who reported symptoms later completed surveys on date of illness onset and the duration and severity of their infection and symptoms.

Average participant age was 40.5 years, 61.0% were men, 70.4% had no underlying medical conditions, and 77.1% were unvaccinated at the time of their infection. Full vaccination was considered completion of a primary vaccine series.

41% lower risk after post-infection vaccination

Among the 1,832 participants, 236 (12.9%) were hospitalized for COVID-19 and 39.7% were ill for at least 28 days, with 19.9% each sick for at least 90 days and 364 days. The most common moderate or severe symptoms 1 month after illness onset were fatigue (6.5%), exercise intolerance (5.9%), difficulty breathing (4.7%), loss of sense of smell and/or taste (5.3%), and cough (3.8%). Of the 62.1% who completed a 6-month survey, 9.8% said they still had at least one COVID-related symptom.

Risk factors for persistent symptoms at 28 days included being unvaccinated at infection (risk ratio [RR], 1.39), moderate (RR, 1.80) or severe (RR, 2.25) acute illness, longer hospital stays (RR for each day, 1.02), and a Charlson Comorbidity Index (CCI) score of at least 5, indicating severe underlying illnesses (RR, 1.55).

At 90 days post-infection, the results were similar, except that vaccination and a CCI score of at least 5 were no longer linked to lingering symptoms. Infection during the Delta wave weren't tied to symptoms lasting 90 days or longer (RR, 0.68). A sensitivity analysis using an alternative model found that hospitalized patients had a 38% higher risk of symptoms lasting at least 28 days than their nonhospitalized peers (RR, 1.38).

Unvaccinated participants who received at least one vaccine dose 1 to 12 months after infection were at an estimated 41% lower risk of still having symptoms at 6 months (RR, 0.59), and greater disease severity was associated with ongoing symptoms.

Increased healthcare use at 6 months

All participants had a higher risk of diabetes (RR, 1.46) and lung- (RR, 2.00), neurologic- (RR, 1.29), and mental illness-related healthcare visits 6 months after symptom onset than before infection. Women and those infected during the Delta surge were particularly likely to seek care for these conditions.

A sensitivity analysis using an alternative model found that hospitalized patients had a 38% higher risk of symptoms lasting at least 28 days than their nonhospitalized peers.

Patients who were unvaccinated before infection had a higher probability of seeking care for lung (RR, 1.72) and neurologic (RR, 1.27) conditions than their vaccinated counterparts, as did those who were older or in a higher body mass index (BMI) category and those who had been hospitalized.

"We also noted a high frequency of medical encounters for other organ system diagnoses up to several months after symptom onset," the study authors wrote. "Taken together, this represents a substantive burden of medical care utilization after COVID-19, even after adjusting for health care use prior to COVID-19 infection."

The researchers said that future studies are needed to confirm the link between postinfection vaccination and lower risk of long-COVID symptoms, as well as the mechanisms behind it. "The observations of postinfection vaccination benefit may reflect enhanced clearance of persistent virus or nonspecific immunomodulation, which may alter possible inflammatory drivers of PCC [post COVID-19 conditions] symptoms," they wrote.

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